Pyrimidine ether derivatives and methods of use thereof

ABSTRACT

The present invention relates to Pyrimidine Ether Derivatives, compositions comprising a Pyrimidine Ether Derivative, and methods of using the Pyrimidine Ether Derivatives for treating or preventing obesity, diabetes, a metabolic disorder, a cardiovascular disease or a disorder related to the activity of a G-protein coupled receptor (GPCR) in a patient.

FIELD OF THE INVENTION

The present invention relates to Pyrimidine Ether Derivatives,compositions comprising a Pyrimidine Ether Derivative, and methods ofusing the Pyrimidine Ether Derivatives for treating or preventingobesity, diabetes, a diabetic complication, a metabolic disorder, acardiovascular disease or a disorder related to the activity of a Gprotein-coupled receptor (GPCR) in a patient.

BACKGROUND OF THE INVENTION

Although a number of receptor classes exist in humans, by far the mostabundant and therapeutically relevant is represented by the Gprotein-coupled receptor class. It is estimated that there are some100,000 genes within the human genome, and of these, approximately 2% or2,000 genes, are estimated to code for GPCRs. Receptors, includingGPCRs, for which the endogenous ligand has been identified are referredto as “known” receptors, while receptors for which the endogenous ligandhas not been identified are referred to as “orphan” receptors. GPCRsrepresent an important area for the development of pharmaceuticalproducts, as evidenced by the fact that pharmaceutical products havebeen developed from approximately 20 of the 100 known GPCRs. Thisdistinction is not merely semantic, particularly in the case of GPCRs.Thus, the orphan GPCRs are to the pharmaceutical industry what gold wasto California in the late 19th century—an opportunity to drive growth,expansion, enhancement and development.

GPCRs share a common structural motif. All these receptors have sevensequences of between 22 to 24 hydrophobic amino acids that form sevenalpha helices, each of which spans the membrane (each span is identifiedby number, i.e., transmembrane-1 (TM-1), transmembrane-2 (TM-2), etc.).The transmembrane helices are joined by strands of amino acids betweentransmembrane-2 and transmembrane-3, transmembrane-4 andtransmembrane-5, and transmembrane-6 and transmembrane-7 on theexterior, or “extracellular” side, of the cell membrane (these arereferred to as “extracellular” regions 1, 2 and 3 (EC-1, EC-2 and EC-3),respectively). The transmembrane helices are also joined by strands ofamino acids between transmembrane-1 and transmembrane-2, transmembrane-3and transmembrane-4, and transmembrane-5 and transmembrane-6 on theinterior, or “intracellular” side, of the cell membrane (these arereferred to as “intracellular” regions 1, 2 and 3 (IC-1, IC-2 and IC-3),respectively). The “carboxy” (“C”) terminus of the receptor lies in theintracellular space within the cell, and the “amino” (“N”) terminus ofthe receptor lies in the extracellular space outside of the cell.

Generally, when an endogenous ligand binds with the receptor (oftenreferred to as “activation” of the receptor), there is a change in theconformation of the intracellular region that allows for couplingbetween the intracellular region and an intracellular “G-protein.” Ithas been reported that GPCRs are “promiscuous” with respect to Gproteins, i.e., that a GPCR can interact with more than one G protein.See, Kenakin, T., Life Sciences 43, 1095 (1988). Although other Gproteins exist, currently, Gq, Gs, Gi, and Go are G proteins that havebeen identified. Endogenous ligand-activated GPCR coupling with theG-protein begins a signaling cascade process (referred to as “signaltransduction”). Under normal conditions, signal transduction ultimatelyresults in cellular activation or cellular inhibition. It is thoughtthat the IC-3 loop as well as the carboxy terminus of the receptorinteract with the G protein.

Under physiological conditions, GPCRs exist in the cell membrane inequilibrium between two different conformations: an “inactive” state andan “active” state. A receptor in an inactive state is unable to link tothe intracellular signaling transduction pathway to produce a biologicalresponse. Changing the receptor conformation to the active state allowslinkage to the transduction pathway (via the G-protein) and produces abiological response. A receptor can be stabilized in an active state byan endogenous ligand or a compound such as a drug.

Modulation of G-protein coupled receptors has been well-studied forcontrolling various metabolic disorders. Small molecule modulators ofthe receptor GPR119, a G-protein coupled-receptor described in, forexample, GenBank (see, e.g., accession numbers XM.sub.-066873 andAY288416), have been shown to be useful for treating or preventingcertain metabolic disorders. GPR119 is a G protein-coupled receptor thatis selectively expressed on pancreatic beta cells. GPR119 activationleads to elevation of a level of intracellular cAMP, consistent withGPR119 being coupled to Gs. Agonists to GPR119 stimulateglucose-dependent insulin secretion in vitro and lower an elevated bloodglucose level in vivo. See, e.g., International Publication Nos. WO04/065380, WO 04/076413, and EP 1338651, the disclosure of each of whichis herein incorporated by reference in its entirety.

U.S. Ser. No. 10/890,549 discloses pyrazolo[3,4-d]pyrimidine ethers andrelated compounds as modulators of the GPR119 receptor that are usefulfor the treatment of various metabolic-related disorders such as type Idiabetes, type II diabetes, inadequate glucose tolerance, insulinresistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia or syndrome X. The compounds are alsoreported as being useful for controlling weight gain, controlling foodintake, and inducing satiety in mammals. The promising nature of theseGPCR modulators indicates a need in the art for additional smallmolecule GPCR modulators with improved efficacy and safety profiles.This invention addresses that need.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides compounds of Formula (I):

and pharmaceutically acceptable salts, solvates, esters and prodrugsthereof, wherein:

A is alkylene, —O—, —N(R⁴)—, —S— or —O-alkylene-;

B is:

J is —C(R⁵)— or —N—;

L is —C(R⁵)— or —N—;

M is —C(R⁵)— or —N—;

Q is a bond, alkylene, —C(O)—, —C(O)—O—, —S(O)₂—, —S(O)₂—N(R⁸)— or—C(O)—N(R¹⁰)—;

W is a bond, alkylene, —C(O)—, —C(O)—O—, —S(O)₂—, —S(O)₂—N(R⁸)— or—C(O)—N(R¹⁰)—;

X is alkylene, —O—, —N(R⁴)—, —S— or —O-alkylene-, such that X can be inan endo- or exo-configuration with respect to its point of attachment togroup B;

Y is H, halo, —CN, alkyl, —O-alkyl, —S-alkyl or —S(O)₂-alkyl;

Z is a bond, —C(R¹)₂—, —O—, —N(R⁴)—, —S(O)₂— or —S—;

each occurrence of R¹ is independently H, alkyl, halo or —OH; or any twogeminal R¹ groups, together with the common carbon atom to which theyare attached, join to form a spirocyclic 3- to 6-membered cycloalkylgroup, a spirocyclic 3- to 6-membered heterocycloalkyl group or aspirocyclic 3- to 6-membered heterocycloalkenyl group; or any two R¹groups present on adjacent carbon atoms, together with the adjacentcarbon atoms to which they are attached, join to form a fused 3- to6-membered cycloalkyl group, a fused 3- to 6-membered heteroaryl groupor a fused aryl group; and wherein an alkyl group can be unsubstitutedor optionally substituted with one or more of the following groups:—O-alkyl, —OH or —N(R⁴)₂; and wherein an optional endocyclic double bondcan be present between any two adjacent ring carbon atoms;

each occurrence of R² is independently H, alkyl, halo or —OR⁷;

R³ is alkyl, alkenyl, alkynyl, haloalkyl, -(alkylene)_(t)-aryl,-(alkylene)_(t)-cycloalkyl, -(alkylene)_(t)-cycloalkenyl,-(alkylene)_(t)-heterocycloalkyl, -(alkylene)_(t)-heterocycloalkenyl or-(alkylene)_(t)-heteroaryl, wherein an aryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl or heteroaryl group can beunsubstituted or optionally substituted with up to four R⁷ groups, whichcan be the same or different;

each occurrence of R⁴ is independently H, alkyl or aryl;

each occurrence of R⁵ is independently H, —N(R⁴)₂, halo, cycloalkyl,alkyl or aryl;

each occurrence of R⁶ is independently H or alkyl;

each occurrence of R⁷ is independently selected from: from alkenyl,alkynyl, halo, haloalkyl, —CN, —NO₂, —O-(alkylene)_(t)-R⁹,—S-(alkylene)_(t)-R⁹, —N(R⁹)-(alkylene)_(t)-R⁹, -(alkylene)_(t)-R⁹,—C(O)-(alkylene)_(t)-R⁹, —C(O)O-(alkylene)_(t)-R⁹,—N(R⁶)C(O)-(alkylene)_(t)-R⁹, —C(O)N(R⁶)-(alkylene)_(t)-R⁹,—OC(O)-(alkylene)_(t)-R⁹, —N(R⁶)C(O)N(R⁶)-(alkylene)_(t)-R⁹,—N(R⁶)C(O)O-(alkylene)_(t)-R⁹, —S(O)-(alkylene)_(t)-R⁹ and—S(O)₂(alkylene)_(t)-R⁹;

R⁸ is H, alkyl, aryl or —C(O)OR⁴;

each occurrence of R⁹ is independently H, haloalkyl, aryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl;

R¹⁰ is alkyl, alkenyl, alkynyl, haloalkyl, -(alkylene)_(t)-aryl,-(alkylene)_(t)-cycloalkyl, -(alkylene)_(t)-cycloalkenyl,-(alkylene)_(t)-heterocycloalkyl, -(alkylene)_(t)-heterocycloalkenyl or-(alkylene)_(t)-heteroaryl, wherein an aryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl or heteroaryl group can beunsubstituted or optionally substituted with up to four R⁷ groups, whichcan be the same or different;

d is 0, 1 or 2;

e is 0, 1 or 2;

f is 0, 1 or 2;

g is 0, 1 or 2, such that the sum of d, e, f and g is an integer rangingfrom 2 to 6;

p is 0, 1 or 2;

q is 0, 1 or 2;

r is 1 or 2;

s is 1 or 2;

each occurrence of t is independently 0 or 1; and

u is 0, 1 or 2.

The Compounds of Formula (I) and pharmaceutically acceptable salts,solvates, esters or prodrugs thereof (referred to collectively herein asthe “Pyrimidine Ether Derivatives”) can be useful for treating orpreventing obesity, diabetes, a diabetic complication, metabolicsyndrome, a cardiovascular disease, or a disorder related to theactivity of a GPCR (each being a “Condition”) in a patient.

Also provided by the invention are methods for treating or preventing aCondition in a patient, comprising administering to the patient aneffective amount of one or more Pyrimidine Ether Derivatives.

The present invention further provides compositions comprising aneffective amount of one or more Pyrimidine Ether Derivatives or apharmaceutically acceptable salt, solvate, ester or prodrug thereof, anda pharmaceutically acceptable carrier. The compositions can be usefulfor treating or preventing a Condition in a patient.

The details of the invention are set forth in the accompanying detaileddescription below.

Although any methods and materials similar to those described herein canbe used in the practice or testing of the present invention,illustrative methods and materials are now described. Other features,objects, and advantages of the invention will be apparent from thedescription and the claims. All patents and publications cited in thisspecification are incorporated herein by reference.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides Pyrimidine Ether Derivatives of Formula(I), compositions comprising one or more Pyrimidine Ether Derivatives,and methods of using the Pyrimidine Ether Derivatives for treating orpreventing a Condition in a patient.

Definitions and Abbreviations

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

A “patient” is a human or non-human mammal. In one embodiment, a patientis a human. In another embodiment, a patient is a non-human mammal,including, but not limited to, a monkey, dog, baboon, rhesus, mouse,rat, horse, cat or rabbit. In another embodiment, a patient is acompanion animal, including but not limited to a dog, cat, rabbit, horseor ferret. In one embodiment, a patient is a dog. In another embodiment,a patient is a cat.

The term “obesity” as used herein, refers to a patient being overweightand having a body mass index (BMI) of 25 or greater. In one embodiment,an obese patient has a BMI of 25 or greater. In another embodiment, anobese patient has a BMI from 25 to 30. In another embodiment, an obesepatient has a BMI greater than 30. In still another embodiment, an obesepatient has a BMI greater than 40.

The term “obesity-related disorder” as used herein refers to: (i)disorders which result from a patient having a BMI of 25 or greater; and(ii) eating disorders and other disorders associated with excessive foodintake. Non-limiting examples of an obesity-related disorder includeedema, shortness of breath, sleep apnea, skin disorders and high bloodpressure.

The term “metabolic syndrome” as used herein, refers to a set of riskfactors that make a patient more succeptible to cardiovascular diseaseand/or type 2 diabetes. A patient is said to have metabolic syndrome ifthe patient simultaneously has three or more of the following five riskfactors:

-   -   1) central/abdominal obesity as measured by a waist        circumference of greater than 40 inches in a male and greater        than 35 inches in a female;    -   2) a fasting triglyceride level of greater than or equal to 150        mg/dL;    -   3) an HDL cholesterol level in a male of less than 40 mg/dL or        in a female of less than 50 mg/dL;    -   4) blood pressure greater than or equal to 130/85 mm Ng; and    -   5) a fasting glucose level of greater than or equal to 110        mg/dL.

The term “effective amount” as used herein, refers to an amount of aPyrimidine Ether Derivative and/or an additional therapeutic agent, or acomposition thereof, that is effective in producing the desiredtherapeutic, ameliorative, inhibitory or preventative effect whenadministered to a patient suffering from a Condition. In the combinationtherapies of the present invention, an effective amount can refer toeach individual agent or to the combination as a whole, wherein theamounts of all agents administered are together effective, but whereinthe component agent of the combination may not be present individuallyin an effective amount.

The term “alkyl,” as used herein, refers to an aliphatic hydrocarbongroup which may be straight or branched and which contains from about 1to about 20 carbon atoms. In one embodiment, an alkyl group containsfrom about 1 to about 12 carbon atoms. In another embodiment, an alkylgroup contains from about 1 to about 6 carbon atoms. Non-limitingexamples of alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, isobutyl, tent-butyl, n-pentyl, neopentyl,isopentyl, n-hexyl, isohexyl and neohexyl. An alkyl group may beunsubstituted or substituted by one or more substituents which may bethe same or different, each substituent being independently selectedfrom the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl,cyano, hydroxy, —O-alkyl, —O-aryl, -alkylene-O-alkyl, alkylthio, —NH₂,—NH(alkyl), —N(alkyl)₂, —NH(cycloalkyl), —O—C(O)-alkyl, —O—C(O)-aryl,—O—C(O)-cycloalkyl, —C(O)OH and —C(O)O-alkyl. In one embodiment, analkyl group is unsubstituted. In another embodiment, an alkyl group islinear. In another embodiment, an alkyl group is branched.

The term “alkenyl,” as used herein, refers to an aliphatic hydrocarbongroup containing at least one carbon-carbon double bond and which may bestraight or branched and contains from about 2 to about 15 carbon atoms.In one embodiment, an alkenyl group contains from about 2 to about 12carbon atoms. In another embodiment, an alkenyl group contains fromabout 2 to about 6 carbon atoms. Non-limiting examples of alkenyl groupsinclude ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl,octenyl and decenyl. An alkenyl group may be unsubstituted orsubstituted by one or more substituents which may be the same ordifferent, each substituent being independently selected from the groupconsisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy,—O-alkyl, —O-aryl, -alkylene-O-alkyl, alkylthio, —NH₂, —NH(alkyl),—N(alkyl)₂, —NH(cycloalkyl), —O—C(O)-alkyl, —O—C(O)-aryl,—O—C(O)-cycloalkyl, —C(O)OH and —C(O)O-alkyl. In one embodiment, analkenyl group is unsubstituted.

The term “alkynyl,” as used herein, refers to an aliphatic hydrocarbongroup containing at least one carbon-carbon triple bond and which may bestraight or branched and contains from about 2 to about 15 carbon atoms.In one embodiment, an alkynyl group contains from about 2 to about 12carbon atoms. In another embodiment, an alkynyl group contains fromabout 2 to about 6 carbon atoms. Non-limiting examples of alkynyl groupsinclude ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. An alkynylgroup may be unsubstituted or substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of halo, alkenyl, alkynyl, aryl,cycloalkyl, cyano, hydroxy, —O-alkyl, —O-aryl, -alkylene-O-alkyl,alkylthio, —NH₂, —NH(alkyl), —N(alkyl)₂, —NH(cycloalkyl), —O—C(O)-alkyl,—O—C(O)-aryl, —O—C(O)-cycloalkyl, —C(O)OH and —C(O)O-alkyl. In oneembodiment, an alkynyl group is unsubstituted.

The term “alkylene,” as used herein, refers to an alkyl group, asdefined above, wherein one of the alkyl group's hydrogen atoms has beenreplaced with a bond. Non-limiting examples of alkylene groups include—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH(CH₃)CH₂CH₂—, —CH(CH₃)—and —CH₂CH(CH₃)CH₂—. In one embodiment, an alkylene group has from 1 toabout 6 carbon atoms. In another embodiment, an alkylene group isbranched. In another embodiment, an alkylene group is linear.

The term “aryl,” as used herein, refers to an aromatic monocyclic ormulticyclic ring system comprising from about 6 to about 14 carbonatoms. In one embodiment, an aryl group contains from about 6 to about10 carbon atoms. An aryl group can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined herein below. Non-limiting examples of aryl groupsinclude phenyl and naphthyl. In one embodiment, an aryl group isunsubstituted. In another embodiment, an aryl group is phenyl.

The term “cycloalkyl,” as used herein, refers to a non-aromatic mono- ormulticyclic ring system comprising from about 3 to about 10 ring carbonatoms. In one embodiment, a cycloalkyl contains from about 5 to about 10ring carbon atoms. In another embodiment, a cycloalkyl contains fromabout 3 to about 7 ring atoms. In another embodiment, a cycloalkylcontains from about 5 to about 7 ring atoms. The term “cycloalkyl” alsoencompasses a cycloalkyl group, as defined above, which is fused to anaryl (e.g., benzene) or heteroaryl ring. Non-limiting examples ofmonocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl. Non-limiting examples ofmulticyclic cycloalkyls include 1-decalinyl, norbornyl and adamantyl. Acycloalkyl group can be optionally substituted with one or more “ringsystem substituents” which may be the same or different, and are asdefined herein below. In one embodiment, a cycloalkyl group isunsubstituted.

The term “cycloalkenyl,” as used herein, refers to a non-aromatic mono-or multicyclic ring system comprising from about 3 to about 10 ringcarbon atoms and containing at least one endocyclic double bond. In oneembodiment, a cycloalkenyl contains from about 5 to about 10 ring carbonatoms. In another embodiment, a cycloalkenyl contains 5 or 6 ring atoms.Non-limiting examples of monocyclic cycloalkenyls include cyclopentenyl,cyclohexenyl, cyclohepta-1,3-dienyl, and the like. A cycloalkenyl groupcan be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedherein below. In one embodiment, a cycloalkenyl group is unsubstituted.In another embodiment, a cycloalkenyl group is a 6-memberedcycloalkenyl. In another embodiment, a cycloalkenyl group is a5-membered cycloalkenyl.

The term “heteroaryl,” as used herein, refers to an aromatic monocyclicor multicyclic ring system comprising about 5 to about 14 ring atoms,wherein from 1 to 4 of the ring atoms is independently O, N or S and theremaining ring atoms are carbon atoms. In one embodiment, a heteroarylgroup has 5 to 10 ring atoms. In another embodiment, a heteroaryl groupis monocyclic and has 5 or 6 ring atoms. A heteroaryl group can beoptionally substituted by one or more “ring system substituents” whichmay be the same or different, and are as defined herein below. Aheteroaryl group is joined via a ring carbon atom, and any nitrogen atomof a heteroaryl can be optionally oxidized to the corresponding N-oxide.The term “heteroaryl” also encompasses a heteroaryl group, as definedabove, which is fused to a benzene ring. Non-limiting examples ofheteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl,pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl,oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like. In oneembodiment, a heteroaryl group is unsubstituted. In another embodiment,a heteroaryl group is a 5-membered heteroaryl. In another embodiment, aheteroaryl group is a 6-membered heteroaryl.

The term “heterocycloalkyl,” as used herein, refers to a non-aromaticsaturated monocyclic or multicyclic ring system comprising 3 to about 10ring atoms, wherein from 1 to 4 of the ring atoms are independently O, Sor N and the remainder of the ring atoms are carbon atoms. In oneembodiment, a heterocycloalkyl group has from about 5 to about 10 ringatoms. In another embodiment, a heterocycloalkyl group has 5 or 6 ringatoms. There are no adjacent oxygen and/or sulfur atoms present in thering system. Any —NH group in a heterocycloalkyl ring may existprotected such as, for example, as an —N(BOC), —N(Cbz), —N(Tos) groupand the like; such protected heterocycloalkyl groups are considered partof this invention. The term “heterocycloalkyl” also encompasses aheterocycloalkyl group, as defined above, which is fused to an aryl(e.g., benzene) or heteroaryl ring. A heterocycloalkyl group can beoptionally substituted by one or more “ring system substituents” whichmay be the same or different, and are as defined herein below. Thenitrogen or sulfur atom of the heterocycloalkyl can be optionallyoxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.Non-limiting examples of monocyclic heterocycloalkyl rings includepiperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl,thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl,lactam, lactone, and the like. A ring carbon atom of a heterocycloalkylgroup may be functionalized as a carbonyl group. An illustrative exampleof such a heterocycloalkyl group is pyrrolidonyl:

In one embodiment, a heterocycloalkyl group is unsubstituted. In anotherembodiment, a heterocycloalkyl group is a 5-membered heterocycloalkyl.In another embodiment, a heterocycloalkyl group is a 6-memberedheterocycloalkyl.

The term “heterocycloalkenyl,” as used herein, refers to aheterocycloalkyl group, as defined above, wherein the heterocycloalkylgroup contains from 3 to 10 ring atoms, and at least one endocycliccarbon-carbon or carbon-nitrogen double bond. In one embodiment, aheterocycloalkenyl group has from 5 to 10 ring atoms. In anotherembodiment, a heterocycloalkenyl group is monocyclic and has 5 or 6 ringatoms. A heterocycloalkenyl group can optionally substituted by one ormore ring system substituents, wherein “ring system substituent” is asdefined above. The nitrogen or sulfur atom of the heterocycloalkenyl canbe optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of heterocycloalkenyl groups include1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl,1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl,2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl,dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl,dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl,fluoro-substituted dihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,dihydrothiophenyl, dihydrothiopyranyl, and the like. A ring carbon atomof a heterocycloalkenyl group may be functionalized as a carbonyl group.An illustrative example of such a heterocycloalkenyl group is:

In one embodiment, a heterocycloalkenyl group is unsubstituted. Inanother embodiment, a heterocycloalkenyl group is a 6-memberedheterocycloalkenyl. In another embodiment, a heterocycloalkenyl group isa 5-membered heterocycloalkenyl.

The term “ring system substituent,” as used herein, refers to asubstituent group attached to an aromatic or non-aromatic ring systemwhich, for example, replaces an available hydrogen on the ring system.Ring system substituents may be the same or different, each beingindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, -alkyl-aryl, -aryl-alkyl,-alkylene-heteroaryl, -alkenylene-heteroaryl, -alkynylene-heteroaryl,hydroxy, hydroxyalkyl, haloalkyl, —O-alkyl, —O-haloalkyl,-alkylene-O-alkyl, —O-aryl, aralkoxy, acyl, aroyl, halo, nitro, cyano,carboxy, —C(O)O-alkyl, —C(O)O-aryl, —C(O)O-alkelene-aryl, —S(O)-alkyl,—S(O)₂-alkyl, —S(O)-aryl, —S(O)₂-aryl, —S(O)-heteroaryl,—S(O)₂-heteroaryl, —S-alkyl, —S-aryl, —S-heteroaryl, —S-alkylene-aryl,—S-alkylene-heteroaryl, cycloalkyl, heterocycloalkyl, —O—C(O)-alkyl,—O—C(O)-aryl, —O—C(O)-cycloalkyl, —C(═N—CN)—NH₂, —C(═NH)—NH₂,—C(═NH)—NH(alkyl), Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)—, Y₁Y₂NS(O)₂— and—S(O)₂NY₁Y₂, wherein Y₁ and Y₂ can be the same or different and areindependently selected from the group consisting of hydrogen, alkyl,aryl, cycloalkyl, and -alkylene-aryl. “Ring system substituent” may alsomean a single moiety which simultaneously replaces two availablehydrogens on two adjacent carbon atoms (one H on each carbon) on a ringsystem. Examples of such moiety are methylenedioxy, ethylenedioxy,—C(CH₃)₂— and the like which form moieties such as, for example:

“Halo” means —F, —Cl, —Br or —I. In one embodiment, halo refers to —F,—Cl or —Br.

The term “haloalkyl,” as used herein, refers to an alkyl group asdefined above, wherein one or more of the alkyl group's hydrogen atomshas been replaced with a halogen. In one embodiment, a haloalkyl grouphas from 1 to 6 carbon atoms. In another embodiment, a haloalkyl groupis substituted with from 1 to 3 F atoms. Non-limiting examples ofhaloalkyl groups include —CH₂F, —CHF₂, —CF₃, —CH₂Cl and —CCl₃.

The term “hydroxyalkyl,” as used herein, refers to an alkyl group asdefined above, wherein one or more of the alkyl group's hydrogen atomshas been replaced with an —OH group. In one embodiment, a hydroxyalkylgroup has from 1 to 6 carbon atoms. Non-limiting examples ofhydroxyalkyl groups include —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH and—CH₂CH(OH)CH₃.

The term “alkoxy” as used herein, refers to an —O-alkyl group, whereinan alkyl group is as defined above. Non-limiting examples of alkoxygroups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy andt-butoxy. An alkoxy group is bonded via its oxygen atom.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “purified”, “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of the compound afterbeing isolated from a synthetic process (e.g. from a reaction mixture),or natural source or combination thereof. Thus, the term “purified”, “inpurified form” or “in isolated and purified form” for a compound refersto the physical state of the compound after being obtained from apurification process or processes described herein or well known to theskilled artisan (e.g., chromatography, recrystallization and the like),in sufficient purity to be characterizable by standard analyticaltechniques described herein or well known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and Tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene at al, Protective Groups in Organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in Formula (I), its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g, a drugprecursor) that is transformed in vivo to yield a Pyrimidine EtherDerivative or a pharmaceutically acceptable salt, hydrate or solvate ofthe compound. The transformation may occur by various mechanisms (e.g.,by metabolic or chemical processes), such as, for example, throughhydrolysis in blood. A discussion of the use of prodrugs is provided byT. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987.

For example, if a Pyrimidine Ether Derivative or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di (C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a Pyrimidine Ether Derivative contains an alcoholfunctional group, a prodrug can be formed by the replacement of thehydrogen atom of the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N-(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkyl, α-amino(C₁-C₄)alkylene-aryl, arylacyl andα-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group isindependently selected from the naturally occurring L-amino acids,P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting fromthe removal of a hydroxyl group of the hemiacetal form of acarbohydrate), and the like.

If a Pyrimidine Ether Derivative incorporates an amine functional group,a prodrug can be formed by the replacement of a hydrogen atom in theamine group with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl,—C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl or benzyl, —C(OY²)Y³ whereinY² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl, carboxy (C₁-C₆)alkyl,amino(C₁-C₄)alkyl or mono-N- or di-N,N-(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵wherein Y⁴ is H or methyl and Y⁵ is mono-N- or di-N,N-(C₁-C₆)alkylaminomorpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of solvates includeethanolates, methanolates, and the like. A “hydrate” is a solvatewherein the solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTechours., 5(1), article 12 (2004); and A. L. Binghamet al, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

The Pyrimidine Ether Derivatives can form salts which are also withinthe scope of this invention. Reference to a Pyrimidine Ether Derivativeherein is understood to include reference to salts thereof, unlessotherwise indicated. The term “salt(s)”, as employed herein, denotesacidic salts formed with inorganic and/or organic acids, as well asbasic salts formed with inorganic and/or organic bases. In addition,when a Pyrimidine Ether Derivative contains both a basic moiety, suchas, but not limited to a pyridine or imidazole, and an acidic moiety,such as, but not limited to a carboxylic acid, zwitterions (“innersalts”) may be formed and are included within the term “salt(s)” as usedherein. In one embodiment, the salt is a pharmaceutically acceptable(i.e., non-toxic, physiologically acceptable) salt. In anotherembodiment, the salt is other than a pharmaceutically acceptable salt.Salts of the compounds of the Formula (I) may be formed, for example, byreacting a Pyrimidine Ether Derivative with an amount of acid or base,such as an equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamine, choline, t-butyl amine, andsalts with amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g., decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy group of a hydroxyl compound, in which the non-carbonylmoiety of the carboxylic acid portion of the ester grouping is selectedfrom straight or branched chain alkyl (for example, methyl, ethyl,n-propyl, isopropyl, t-butyl, sec-butyl or n-butyl), alkoxyalkyl (forexample, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl(for example, phenoxymethyl), aryl (for example, phenyl optionallysubstituted with, for example, halogen, C₁₋₄alkyl, or C₁₋₄alkoxy oramino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (forexample, methanesulfonyl); (3) amino acid esters (for example, L-valylor L-isoleucyl); (4) phosphonate esters and (5) mono-, di- ortriphosphate esters. The phosphate esters may be further esterified by,for example, a C₁₋₂₀ alcohol or reactive derivative thereof, or by a2,3-di (C₆₋₂₄)acyl glycerol.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers.Sterochemically pure compounds may also be prepared by using chiralstarting materials or by employing salt resolution techniques. Also,some of the Pyrimidine Ether Derivatives may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the Pyrimidine Ether Derivatives may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, hydrates, esters and prodrugs of the compounds as well as thesalts, solvates and esters of the prodrugs), such as those which mayexist due to asymmetric carbons on various substituents, includingenantiomeric forms (which may exist even in the absence of asymmetriccarbons), rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a Pyrimidine Ether Derivative incorporates a double bond or a fusedring, both the cis- and trans-forms, as well as mixtures, are embracedwithin the scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention).

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to apply equally to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled Pyrimidine Ether Derivatives of thepresent invention (e.g., those labeled with ³H and ¹⁴C) are useful incompound and/or substrate tissue distribution assays. In one embodiment,tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes are employed fortheir ease of preparation and detectability. In another embodiment,substitution with heavier isotopes such as deuterium (i.e., ²H) mayafford certain therapeutic advantages resulting from greater metabolicstability (e.g., increased in vivo half-life or reduced dosagerequirements). In one embodiment, one or more hydrogen atoms of aPyrimidine Ether Derivative of the present invention is replaced by adeuterium atom. Isotopically labelled Pyrimidine Ether Derivatives ofthe present invention can generally be prepared by following proceduresanalogous to those disclosed in the Schemes and/or in the Examplesherein below, by substituting an appropriate isotopically labelledreagent for a non-isotopically labelled reagent.

Polymorphic forms of the Pyrimidine Ether Derivatives, and of the salts,solvates, hydrates, esters and prodrugs of the Pyrimidine EtherDerivatives, are intended to be included in the present invention.

The following abbreviations are used below and have the followingmeanings: AcOH is acetic acid, Boc is —C(O)O-(t-butyl), Bn is benzyl,Bn-NH₂ is benzylamine, t-butyl is tertiary butyl, DBU is1,8-diazabicyclo[5.4.0]undec-7-ene, DMEM is Dulbecco's modified eaglemedium, DMSO is dimethylsulfoxide, EtOAc is ethyl acetate, EtOH isethanol, Et₃N is triethylamine, HEPES is 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, LCMS is liquid chromatography mass spectrometry, Meis methyl, MeOH is methanol, NMR is nuclear magnetic resonance,Pd(OH)₂/C is palladium hydroxide on carbon, Ph is phenyl, THF istetrahydrofuran and TLC is thin-layer chromatography.

The Pyrimidine Ether Derivatives of Formula (I)

The present invention provides Pyrimidine Ether Derivatives of Formula(I):

and pharmaceutically acceptable salts, solvates, esters, prodrugs andstereoisomers thereof, wherein A, B, J, L, M, W, X, Y, R¹, R³, d, e, fand g are defined above for the Compounds of Formula (I).

In one embodiment, d, e, f and g are each 1.

In another embodiment, three of variables d, e, f and g are each 1 andthe remaining variable is 0.

In another embodiment, three of variables d, e, f and g are each 1 andthe remaining variable is 2.

In still another embodiment, two of variables d, e, f and g are each 1and the remaining two variables are each 0.

In another embodiment, the sum of d, e, f and g is 2.

In yet another embodiment, the sum of d, e, f and g is 3.

In another embodiment, the sum of d, e, f and g is 4.

In a further embodiment, the sum of d, e, f and g is 5.

In one embodiment, r and s are each 1.

In another embodiment, p and u are each 0.

In another embodiment, q is 0.

In still another embodiment, q is 1.

In another embodiment, p and u are each 0 and r and s are each 1.

In another embodiment, p and u are each 0 and q, r and s are each 1.

In yet another embodiment, p, q and u are each 0 and r and s are each 1.

In one embodiment, A is —O—.

In another embodiment, A is alkylene.

In another embodiment, A is —N(R⁴)—.

In still another embodiment, A is —S—.

In another embodiment, A is —O-alkylene-.

In one embodiment, B is:

In another embodiment, B is:

In another embodiment, B is:

In still another embodiment, B is:

In another embodiment, B is:

In one embodiment, J is —C(R⁵)—.

In another embodiment, J is —CH—.

In another embodiment, J is —N—.

In one embodiment, L is —C(R⁵)—.

In another embodiment, L is —CH—.

In another embodiment, L is —N—.

In one embodiment, M is —C(R⁵)—.

In another embodiment, M is —CH—.

In another embodiment, M is —N—.

In one embodiment, J and L are each —N— and M is —CH—.

In one embodiment, Q is —C(O)O—.

In another embodiment, Q is a bond.

In another embodiment, Q is —C(O)O— or a bond.

In still another embodiment, Q is alkylene.

In another embodiment, Q is —C(O)—.

In yet another embodiment, Q is —C(O)—O—.

In another embodiment, Q is —S(O)₂—.

In another embodiment, Q is —S(O)₂—N(R⁸)—.

In a further embodiment, Q is —C(O)—N(R¹⁰)—.

In one embodiment, W is —C(O)—.

In another embodiment, W is —C(O)O—.

In another embodiment, W is —S(O)₂—.

In still another embodiment, W is —C(O)—, —C(O)O— or —S(O)₂—.

In another embodiment, W is a bond.

In another embodiment, W is alkylene.

In yet another embodiment, W is —C(O)—.

In another embodiment, W is —S(O)₂—N(R⁸)—.

In a further embodiment, W is —C(O)—N(R¹⁰)—.

In one embodiment, X is —O—.

In one embodiment, Y is H.

In another embodiment, Y is alkyl.

In another embodiment, Y is halo.

In still another embodiment, Y is —O-alkyl.

In one embodiment, Y is H, alkyl, halo or —O-alkyl.

In another embodiment, Y is H, methyl, F or —OCH₃.

In another embodiment, Y is H, methyl, methoxy or F.

In another embodiment, Y is methyl, methoxy or F.

In yet another embodiment, Y is methyl.

In another embodiment, Y is methoxy.

In a further embodiment, Y is F.

In one embodiment, Z is a bond.

In another embodiment, Z is —C(R¹)₂—.

In another embodiment, Z is —O—.

In still another embodiment, Z is —N(R⁴)—.

In another embodiment, Z is —S(O)₂—.

In yet another embodiment, Z is —S—.

In one embodiment, Z is —CH₂— and q is 0.

In another embodiment, Z is —O— and q is 1.

In another embodiment, Z is —S(O)₂—; p and u are each 0; and q, r and sare each 1.

In still another embodiment, Z is —O—; p and u are each 0; and q, r ands are each 1.

In another embodiment, Z is —CH₂—; p, q and u are each 0; r and s areeach 1; and q is 0.

In one embodiment, J and L are each —N—; M is —CH—; and Y is H, alkyl,halo or —O-alkyl.

In another embodiment, J and L are each —N—; M is —CH—; and Y is H,methyl, F or —OCH₃.

In another embodiment, J and L are each —N—; M is —CH—; and Y is halo.

In still another embodiment, J and L are each —N—; M is —CH—; and Y isF.

In one embodiment, J and L are each —N—; M is —CH—; Y is H, alkyl, haloor —O-alkyl; and A and X are each —O—.

In another embodiment, J and L are each —N—; M is —CH—; Y is F; and Aand X are each —O—.

In one embodiment, each occurrence of R¹ is H.

In another embodiment, at least one occurrence of R¹ is other than H.

In one embodiment, each occurrence of R² is H.

In another embodiment, each occurrence of R¹ and R² is H.

In one embodiment, R³ is alkyl, haloalkyl, cycloalkyl or-alkylene-O-alkyl.

In another embodiment, R³ is methyl, ethyl, n-propyl, isopropyl,t-butyl, —CF₃, —CH₂CH₂OCH₃, —CH₂CH₂CF₃, cyclopropyl or cyclopentyl.

In one embodiment, R⁶ is H.

In another embodiment, R⁶ is alkyl.

In one embodiment, R¹⁰ is cycloalkyl or heteroaryl, either of which canbe optionally substituted with an alkyl or halo group.

In another embodiment, R¹⁰ is 1-methylcyclopropyl or4-chloropyrimidin-2-yl.

In one embodiment, Q is a bond and R¹⁰ is heteroaryl, which can beoptionally substituted with a halo group.

In another embodiment, Q is a bond and R¹⁰ is 4-chloropyrimidin-2-yl.

In another embodiment, Q is —C(O)O— and R¹⁰ is cycloalkyl, which can beoptionally substituted with an alkyl group.

In still another embodiment, Q is —C(O)O— and R¹⁰ is1-methylcyclopropyl.

In one embodiment, for the Compounds of Formula (I), variables A, B, J,L, M, W, X, Y, R¹, R³, d, e, f and g are selected independently of eachother.

In another embodiment, a Compound of Formula (I) is in purified form.

In one embodiment, a compound of claim 1 has the formula:

wherein:

Q is —C(O)O— or a bond;

W is —C(O)—, —C(O)O— or —S(O)₂—;

Y is halo;

R³ is alkyl, haloalkyl, cycloalkyl or -alkylene-O-alkyl; and

R¹⁰ is cycloalkyl or heteroaryl, either of which can be substituted withan alkyl or halo group.

In one embodiment, for the Compounds of Formula (Ia), Q is —C(O)O—.

In another embodiment, for the Compounds of Formula (Ia), Q is a bond.

In one embodiment, for the Compounds of Formula (Ia), W is —C(O)O—.

In another embodiment, for the Compounds of Formula (Ia), W is —C(O)—.

In another embodiment, for the Compounds of Formula (Ia), W is —S(O)₂—.

In one embodiment, for the Compounds of Formula (Ia), Y is F.

In one embodiment, for the Compounds of Formula (Ia), R³ is alkyl.

In another embodiment, for the Compounds of Formula (Ia), R³ ishaloalkyl.

In another embodiment, for the Compounds of Formula (Ia), R³ iscycloalkyl.

In another embodiment, for the Compounds of Formula (Ia), R³ is-alkylene-O-alkyl.

In one embodiment, for the Compounds of Formula (Ia), R³ is methyl,ethyl, n-propyl, isopropyl, t-butyl, —CF₃, —CH₂CH₂OCH₃, —CH₂CH₂CF₃,cyclopropyl or cyclopentyl.

In another embodiment, for the Compounds of Formula (Ia), R³ is methyl,ethyl, n-propyl, isopropyl, t-butyl, —CF₃, —CH₂CH₂OCH₃, —CH₂CH₂CF₃,cyclopropyl or cyclopentyl, and Y is halo.

In another embodiment, for the Compounds of Formula (Ia), R³ is methyl,ethyl, n-propyl, isopropyl, t-butyl, —CF₃, —CH₂CH₂OCH₃, —CH₂CH₂CF₃,cyclopropyl or cyclopentyl, and Y is F.

In still another embodiment, for the Compounds of Formula (Ia), R³ ismethyl, ethyl, n-propyl, isopropyl, t-butyl, —CF₃, —CH₂CH₂OCH₃,—CH₂CH₂CF₃, cyclopropyl or cyclopentyl; and Y is F; and Q is —C(O)O—.

In another embodiment, for the Compounds of Formula (Ia), R³ is methyl,ethyl, n-propyl, isopropyl, t-butyl, —CF₃, —CH₂CH₂OCH₃, —CH₂CH₂CF₃,cyclopropyl or cyclopentyl; and Y is F; Q is —C(O)O—; and R¹⁰ iscycloalkyl or heteroaryl, either of which can be substituted with analkyl or halo group.

In another embodiment, for the Compounds of Formula (Ia), R³ is methyl,ethyl, n-propyl, isopropyl, t-butyl, —CF₃, —CH₂CH₂OCH₃, —CH₂CH₂CF₃,cyclopropyl or cyclopentyl; and Y is F; Q is —C(O)O—; and R¹⁰ is1-methylcyclopropyl or 4-chloropyrimid in-2-yl.

Non-limiting examples of the Pyrimidine Ether Derivatives of the presentinvention include compounds 1-12 as set forth below:

Compound No Structure LCMS 1

537 (M + H) 2

515 (M + H) 3

619 (M + Na) 4

563 (M + Na) 5

565 (M + Na) 6

591 (M + Na) 7

569 (M + H) 8

581 (M + Na) 9

507 (M + H) 10

529 (M + H) 11

565 (M + Na) 12

529 (M + H)and pharmaceutically acceptable salts, solvates, esters and prodrugsthereof.

Methods for Making the Pyrimidine Ether Derivatives

Methods useful for making the Pyrimidine Ether Derivatives are set forthin the Examples below and generalized in Schemes 1-4. Alternativesynthetic pathways and analogous structures will be apparent to thoseskilled in the art of organic synthesis.

Scheme 1 illustrates a general method useful for making Pyrimidine EtherDerivatives of Formula (I).

wherein A, B, J, L, M, W, X, Y and R³ are defined above for theCompounds of Formula (I).

A dichloroaryl compound of formula i can be coupled with a compound offormula B—XH to provide the compounds of formula ii. A compound offormula ii can be similarly coupled with a compound of formula iii toprovide the compounds of formula iv, which correspond to the Compoundsof Formula (I).

Scheme 2 illustrates a general method useful for making the PyrimidineEther Derivatives of Formula (I), wherein A and X are each —O—; and Bis:

wherein J, L, M, W, Y and R³ are defined above for the Compounds ofFormula (I).

A dichloroaryl compound of formula i can be coupled with a bicyclicalcohol of formula v to provide the compounds of formula vi. A compoundof formula vi can be similarly coupled with a compound of formula vii toprovide the compounds of formula viii, which correspond to the Compoundsof Formula (I), wherein A and X are each —O—; and B is:

Scheme 3 illustrates a general method useful for making Pyrimidine EtherDerivatives of Formula (I) wherein A and X are each —O—; and B is:

wherein A, B, J, L, M, W, X, Y and R³ are defined above for theCompounds of Formula (I).

A dichloroaryl compound of formula i can be coupled with a bicyclicalcohol of formula ix and the resulting coupled product then has its Bocprotecting group removed using HCl to provide the cyclic amine compoundsof formula x. A compound of formula x can then be coupled with acompound of formula xi in the presence of DBU to provide the compoundsof formula xxi. A compound of formula xxi can then be coupled with acompound of formula viii in the presence of NaH to provide the compoundsof formula xxii, which correspond to the Compounds of Formula (I), A andX are each —O—; and B is:

Scheme 4 shows a method useful for making the compound of formulaxxviii, which is useful for making the Compounds of Formula (I)

Compound xxiii is condensed with formaldehyde and benzylamine in thepresence of acid to provide the bicyclic compound of formula xxiv.Compound xxiv is then reduced using sodium borohydride to providealcohol xxv, the benzyl amine group of which is subsequently deprotectedusing catalytic hydrogenation, then reprotected as its Boc derivativexxvi.

The starting materials and reagents depicted in Schemes 1-4 are eitheravailable from commercial suppliers such as Sigma-Aldrich (St. Louis,Mo.) and Acros Organics Co. (Fair Lawn, N.J.), or can be prepared usingmethods well-known to those of skill in the art of organic synthesis.

One skilled in the art will recognize that the synthesis of PyrimidineEther Derivatives may require the need for the protection of certainfunctional groups (i.e., derivatization for the purpose of chemicalcompatibility with a particular reaction condition). Suitable protectinggroups for the various functional groups of the Pyrimidine EtherDerivatives and methods for their installation and removal may be foundin Greene at al., Protective Groups in Organic Synthesis,Wiley-Interscience, New York, (1999).

EXAMPLES

The following examples exemplify illustrative examples of compounds ofthe present invention and are not to be construed as limiting the scopeof the disclosure. Alternative mechanistic pathways and analogousstructures within the scope of the invention may be apparent to thoseskilled in the art.

General Methods

Solvents, reagents, and intermediates that are commercially availablewere used as received. Reagents and intermediates that are notcommercially available were prepared in the manner described below. ¹HNMR spectra were obtained on a Gemini AS-400 (400 MHz) and are reportedas ppm down field from Me₄Si with number of protons, multiplicities, andcoupling constants in Hertz indicated parenthetically. Where LC/MS dataare presented, analyses was performed using an Applied BiosystemsAPI-100 mass spectrometer and Shimadzu SCL-10A LC column: Altechplatinum C18, 3 micron, 33 mm×7 mm ID; gradient flow: 0 min—10% CH₃CN, 5min—95% CH₃CN, 7 min—95% CH₃CN, 7.5 min—10% CH₃CN, 9 min—stop. Theretention time and observed parent ion are given.

Example 1 Preparation of Compound 1

Step A—Synthesis of Compound 1B

To a solution of Compound 1A (0.130 g, 0.535 mmol, prepared as describedin International Application No. WO 09/055331) in THF (4.0 mL) was addedNaH (60% in oil, 0.107 g, 2.67 mmol) and the resulting reaction wasallowed to stir at room temperature for 10 minutes, then was heated toreflux and allowed to stir at this temperature for 1 hour. The reactionwas cooled to room temperature and a solution of4,6-dichloro-5-fluoropyrimidine (0.107 g, 0.42 mmol, commerciallyavailable) in THF (3 mL) was added to the reaction mixture and theresulting reaction was allowed to stir at room temperature for about 2hours. The reaction mixture was quenched with ice-water and extractedwith EtOAc (2×10 mL). The combined organic layers were dried over MgSO₄,filtered and concentrated in vacuo, and the resulting residue waspurified using preparative TLC (35% EtOAC/hexanes) to provide Compound1B (66 mg, 33%).

Step B—Synthesis of Compound 1D

To a solution of Compound 1B (0.066 g, 0.176 mmol) in dichloromethane(2.0 mL) was added 4N HCl in dioxane (1.0 mL) and the resulting reactionwas allowed to stir at room temperature for 30 minutes, The reactionmixture was concentrated in vacuo and to provide a crude intermediatecompound (0.054 g. 0.17 mmol), which was subsequently dissolved indichloromethane (3 ml). To the resulting solution was addedtriethylamine (0.071 ml, 0.51 mmol) and the reaction was allowed to stirat room temperature for 10 minutes. 2,5-dioxopyrrolidin-1-yl1-methylcyclopropyl carbonate 1C (0.034 g, 0.17 mmol, prepared asdescribed in International Publication No. WO 09/055331) was then addedand the resulting reaction was allowed to stir at room temperature for30 minutes. The reaction was quenched with saturated aqueous ammoniumchloride solution and extracted with dichloromethane (2×5 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered,concentrated in vacuo, and the resulting residue was purified usingpreparative TLC (2% MeOH/DCM) to provide Compound 1 D (0.063 g, 98%).

Step C—Synthesis of Compound 1

To a solution of tent-butyl 4-hydroxypiperidine-1-carboxylate (105 mg,0.52 mmol, commercially available) in THF (5.0 mL) was added NaH (60% inoil, 0.107 g, 2.67 mmol) and the resulting reaction was allowed to stirat room temperature for 10 minutes, then was heated to reflux andallowed to stir at this temperature for 1 hour. The reaction mixture wascooled to room temperature and a solution of Compound 1D (0.193 g, 0.52mmol) in THE (5.0 mL) was added to the reaction mixture and theresulting reaction was allowed to stir at room temperature for about 15hours. The reaction mixture was quenched with ice-water and extractedwith EtOAc (2×10 mL). The combined organic layers were dried overanhydrous MgSO₄, filtered, concentrated in vacuo, and the residueobtained was purified using preparative TLC (60% ethyl Acetate/hexanes)to provide Compound 1 (100 mg, 36% yield).

Example 2 Preparation of Compound 2

Step A—Synthesis of Compound 2A

Compound 1 (15 mg, 0.028 mmol) was taken up in 4N HCl in dioxane (1.0mL) and the resulting reaction was allowed to stir at room temperaturefor 1 hour. The reaction mixture was then concentrated in vacuo toprovide Compound 2A as its hydrochloride salt, which was used withoutfurther purification.

Step B—Synthesis of Compound 2

To a solution of Compound 2A (HCl salt) in dichloromethane (1.0 mL) wasadded triethylamine (0.0117 mL, 0.084 mmol) followed by methylsulfonylchloride (0.003 mL, 0.042 mmol) and the resulting reaction was allowedto stir at room temperature for 2 hours. The reaction was then quenchedwith saturated aqueous NH₄Cl solution and extracted with dichloromethane(2×3 mL). The combined organic extracts were concentrated in vacuo andthe resulting residue was purified using preparative TLC (60%EtOAc/hexanes) to provide Compound 2 (12 mg, 83%).

Compounds 3-8, 11 and 12 were made using the method described in Example1 followed by method described in Example 2 and replacing themethanesulfonyl chloride in Example 2 with the appropriate sulfonylchloride.

Example 3 Preparation of Compound 9

To a solution of compound 2A (HCl salt, 15 mg, 0.0317 mmol) indichloromethane (1.0 mL) was added triethylamine (0.013 mL, 0.0951 mmol)followed by isobutyryl chloride (3.7 mg, 0.0349 mmol) and the resultingreaction was allowed to stir at room temperature for 1 hour. Thereaction was then quenched with saturated aqueous NH₄Cl solution andextracted with dichloromethane (2×3 mL). The combined organic extractswere concentrated in vacuo and the resulting residue was purified usingpreparative TLC (60% EtOAc/hexanes) to provide Compound 9 (14 mg, 87%).

Example 4 Preparation of Compound 10

Step A—Synthesis of Compound 4A

To a solution of Compound 1B (60 mg, 0.193 mmol) in dioxane (1.0 mL) wasadded DBU (0.086 mL, 0.58 mmol), followed 2,5-dichloropyrimidine (0.034g, 0.23 mmol) and the resulting reaction was allowed to stir at roomtemperature for about 15 hours. The reaction was then quenched withsaturated aqueous NH₄Cl solution and extracted with dichloromethane (2×3mL). The combined organic extracts were concentrated in vacuo and theresulting residue was purified using preparative TLC (60% EtOAc/hexanes)to provide Compound 4A (13 mg, 17.5%).

Step B—Synthesis of Compound 4B

Compound 4B was prepared using the method described in Example 1, StepC, and replacing compound 1D with compound 4A.

Step C—Synthesis of Compound 10

Compound 10 was prepared using the method described in Example 2, andreplacing compound 1 with compound 4B.

Example 5 cAMP Assay

The ability of illustrative compounds of the invention to activateGPR119 and stimulate increases in cAMP levels was determined using theLANCE™ cAMP kit (Perkin Elmer). HEK293 cells expressing human GPR119were maintained in culture flasks at 37° C./5% CO₂ in DMEM containing10% fetal bovine serum, 100 U/ml Pen/Strep, and 0.5 mg/ml geneticin. Themedia was changed to Optimem and cells were incubated for about 15 hoursat 37° C./5% CO₂. The Optimem was then aspirated and the cells wereremoved from the flasks using room temperature Hank's balanced salinesolution (HBSS). The cells were pelleted using centrifugation (1300 rpm,7 minutes, room temperature), then resuspended in stimulation buffer(HBSS, 0.1% BSA, 5 mM HEPES, 15 μM RO-20) at 2.5×10⁶ cells/mL. AlexaFluor 647-anti cAMP antibody (1:100) was then added to the cellsuspension and incubated for 30 minutes. A representative PyrimidineEther Derivative (6 μl at 2× concentration) in stimulation buffercontaining 2% DMSO were then added to white 384 well Matrix plates. Cellsuspension mix (6 μl) was added to each well and incubated with thePyrimidine Ether Derivative for 30 minutes. A cAMP standard curve wasalso created in each assay according to the kit protocol. Standardconcentrations of cAMP in stimulation buffer (6 μl) were added to white384 well plates. Subsequently, 6 μl of 1:100 anti-cAMP antibody wasadded to each well. Following the 30 minute incubation period, 12 μl ofdetection mix (included in kit) was added to all wells and incubated for2-3 hours at room temperature. Fluorescence was detected on the platesusing an Envision instrument. The level of cAMP in each well isdetermined by extrapolation from the cAMP standard curve.

Using this assay, EC₅₀ values for various illustrative Pyrimidine EtherDerivatives of the present invention were calculated and are presentedbelow, wherein “A”<100 nM, “B”=100-200 nM and “C”=500 nM to 1 μM.

Compound cAMP No. EC₅₀ 1 C 2 B 3 A 4 B 5 A 6 C 7 B 8 B 9 C 10 A 11 A 12A

Example 6 Effect of the Compounds of the Invention in Oral GlucoseTolerance Test

Male C57Bl/6NCrl mice (6-8 week old) were fasted for about 15 hours andrandomly dosed with either vehicle (20% hydroxypropyl-3-cyclodextrin) ora representative compound of the present invention (at 3, 10 or 30mg/kg) via oral gavage (n=8 mice/group). Glucose was administered to theanimals 30 minutes post-dosing (3 g/kg p.o.). Blood glucose was measuredprior to administration of test compound and glucose, and at 20 minutesafter glucose administration using a hand-held glucometer (AscensiaElite, Bayer).

Using this protocol, the effects of various Pyrimidine Ether Derivativesof the present invention were measured and indicate that the PyrimidineEther Derivatives of the present invention are effective in loweringblood glucose levels after glucose challenge.

Selected Pyrimidine Ether Derivatives of the present invention weretested according to this protocol and all compounds tested successfullylowered blood glucose levels at 3 mg/kg.

Uses of the Pyrimidine Ether Derivatives

The Pyrimidine Ether Derivatives are useful in human and veterinarymedicine for treating or preventing a Condition in a patient. Inaccordance with the invention, the Pyrimidine Ether Derivatives can beadministered to a patient in need of treatment or prevention of aCondition.

Treatment of Obesity and Obesity-Related Disorders

The Pyrimidine Ether Derivatives are useful for treating obesity or anobesity-related disorder.

Accordingly, in one embodiment, the invention provides methods fortreating obesity or an obesity-related disorder in a patient, whereinthe method comprises administering to the patient an effective amount ofone or more Pyrimidine Ether Derivatives, or a pharmaceuticallyacceptable salt, solvate, ester, prodrug or stereoisomer thereof.

Treatment of Diabetes

The Pyrimidine Ether Derivatives are useful for treating diabetes in apatient. Accordingly, in one embodiment, the present invention providesa method for treating diabetes in a patient, comprising administering tothe patient an effective amount of one or more Pyrimidine EtherDerivatives.

Non-limiting examples of diabetes treatable or preventable using thePyrimidine Ether Derivatives include, type I diabetes (insulin-dependentdiabetes mellitus), type II diabetes (non-insulin dependent diabetesmellitus), gestational diabetes, autoimmune diabetes, insulinopathies,idiopathic type I diabetes (Type 1b), latent autoimmumne diabetes inadults, early-onset type 2 diabetes (EOD), youth-onset atypical diabetes(YOAD), maturity onset diabetes of the young (MODY),malnutrition-related diabetes, diabetes due to pancreatic disease,diabetes associated with other endocrine diseases (such as Cushing'sSyndrome, acromegaly, pheochromocytoma, glucagonoma, primaryaldosteronism or somatostatinoma), type A insulin resistance syndrome,type B insulin resistance syndrome, lipatrophic diabetes, diabetesinduced by β-cell toxins, and diabetes induced by drug therapy (such asdiabetes induced by antipsychotic agents).

In one embodiment, the diabetes is type I diabetes.

In another embodiment, the diabetes is type II diabetes.

Treatment of a Diabetic Complication

The Pyrimidine Ether Derivatives are useful for treating a diabeticcomplication in a patient. Accordingly, in one embodiment, the presentinvention provides a method for treating a diabetic complication in apatient, comprising administering to the patient an effective amount ofone or more Pyrimidine Ether Derivatives.

Non-limiting examples of diabetic complications treatable or preventableusing the Pyrimidine Ether Derivatives include diabetic cataract,glaucoma, retinopathy, aneuropathy (such as diabetic neuropathy,polyneuropathy, mononeuropathy, autonomic neuropathy, microaluminuriaand progressive diabetic neuropathyl), nephropathy, gangrene of thefeet, immune-complex vasculitis, systemic lupsus erythematosus (SLE),atherosclerotic coronary arterial disease, peripheral arterial disease,nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, joint problems,a skin or mucous membrane complication (such as an infection, a shinspot, a candidal infection or necrobiosis lipoidicadiabeticorumobesity), hyperlipidemia, cataract, hypertension, syndromeof insulin resistance, coronary artery disease, a fungal infection, abacterial infection, and cardiomyopathy.

Treatment of a Metabolic Disorder

The Pyrimidine Ether Derivatives are useful for treating a metabolicdisorder. Accordingly, in one embodiment, the invention provides methodsfor treating a metabolic disorder in a patient, wherein the methodcomprises administering to the patient an effective amount of one ormore Pyrimidine Ether Derivatives, or a pharmaceutically acceptablesalt, solvate, ester, prodrug or stereoisomer thereof.

Non-limiting examples of metabolic disorders treatable include metabolicsyndrome (also known as “Syndrome X”), impaired glucose tolerance,impaired fasting glucose, hypercholesterolemia, hyperlipidemia,hypertriglyceridemia, low HDL levels, hypertension, phenylketonuria,post-prandial lipidemia, a glycogen-storage disease, Gaucher's Disease,Tay-Sachs Disease, Niemann-Pick Disease, ketosis and acidosis.

In one embodiment, the metabolic disorder is hypercholesterolemia.

In another embodiment, the metabolic disorder is hyperlipidemia.

In another embodiment, the metabolic disorder is hypertriglyceridemia.

In still another embodiment, the metabolic disorder is metabolicsyndrome.

In a further embodiment, the metabolic disorder is low HDL levels.

Methods for Treating a Cardiovascular Disease

The Pyrimidine Ether Derivatives are useful for treating or preventing acardiovascular disease in a patient. Accordingly, in one embodiment, thepresent invention provides a method for treating a cardiovasculardisease in a patient, comprising administering to the patient aneffective amount of one or more Pyrimidine Ether Derivatives.

Non-limiting examples of cardiovascular diseases treatable orpreventable using the present methods include atherosclerosis,congestive heart failure, cardiac arrhythmia, myocardial infarction,atrial fibrillation, atrial flutter, circulatory shock, left ventricularhypertrophy, ventricular tachycardia, supraventricular tachycardia,coronary artery disease, angina, infective endocarditis, non-infectiveendocarditis, cardiomyopathy, peripheral artery disease, Reynaud'sphenomenon, deep venous thrombosis, aortic stenosis, mitral stenosis,pulmonic stenosis and tricuspid stenosis.

In one embodiment, the cardiovascular disease is atherosclerosis.

In another embodiment, the cardiovascular disease is congestive heartfailure.

In another embodiment, the cardiovascular disease is coronary arterydisease.

Combination Therapy

In one embodiment, the present invention provides methods for treating aCondition in a patient, the method comprising administering to thepatient one or more Pyrimidine Ether Derivatives, or a pharmaceuticallyacceptable salt, solvate, ester, prodrug or stereoisomer thereof and atleast one additional therapeutic agent that is not a Pyrimidine EtherDerivative, wherein the amounts administered are together effective totreat or prevent a Condition.

Non-limiting examples of additional therapeutic agents useful in thepresent methods for treating or preventing a Condition include,anti-obesity agents, antidiabetic agents, any agent useful for treatingmetabolic syndrome, any agent useful for treating a cardiovasculardisease, cholesterol biosynthesis inhibitors, cholesterol absorptioninhibitors, bile acid sequestrants, probucol derivatives, IBATinhibitors, nicotinic acid receptor (NAR) agonists, ACAT inhibitors,cholesteryl ester transfer proten (CETP) inhibitors, low-densitylipoprotein (LDL) activators, fish oil, water-soluble fibers, plantsterols, plant stanols, fatty acid esters of plant stanols, or anycombination of two or more of these additional therapeutic agents.

Non-limiting examples of anti-obesity agents useful in the presentmethods for treating a Condition include CB1 antagonists or inverseagonists such as rimonabant, neuropeptide Y antagonists, MCR4 agonists,MCH receptor antagonists, histamine H₃ receptor antagonists or inverseagonists, metabolic rate enhancers, nutrient absorption inhibitors,leptin, appetite suppressants and lipase inhibitors.

Non-limiting examples of appetite suppressant agents useful in thepresent methods for treating or preventing a Condition includecannabinoid receptor 1 (CB₁) antagonists or inverse agonists (e.g.,rimonabant); Neuropeptide Y (NPY1, NPY2, NPY4 and NPY5) antagonists;metabotropic glutamate subtype 5 receptor (mGluR5) antagonists (e.g.,2-methyl-6-(phenylethynyl)-pyridine and3[(2-methyl-1,4-thiazol-4-yl)ethynyl]pyridine); melanin-concentratinghormone receptor (MCH1R and MCH2R) antagonists; melanocortin receptoragonists (e.g., Melanotan-II and Mc4r agonists); serotonin uptakeinhibitors (e.g., dexfenfluramine and fluoxetine); serotonin (5HT)transport inhibitors (e.g., paroxetine, fluoxetine, fenfluramine,fluvoxamine, sertaline and imipramine); norepinephrine (NE) transporterinhibitors (e.g., desipramine, talsupram and nomifensine); ghrelinantagonists; leptin or derivatives thereof; opioid antagonists (e.g.,nalmefene, 3-methoxynaltrexone, naloxone and nalterxone); orexinantagonists; bombesin receptor subtype 3 (BRS3) agonists;Cholecystokinin-A (CCK-A) agonists; ciliary neurotrophic factor (CNTF)or derivatives thereof (e.g., butabindide and axokine); monoaminereuptake inhibitors (e.g., sibutramine); glucagon-like peptide 1 (GLP-1)agonists; topiramate; and phytopharm compound 57.

Non-limiting examples of metabolic rate enhancers useful in the presentmethods for treating or preventing a Condition include acetyl-CoAcarboxylase-2 (ACC2) inhibitors; beta adrenergic receptor 3 (β3)agonists; diacylglycerol acyltransferase inhibitors (DGAT1 and DGAT2);fatty acid synthase (FAS) inhibitors (e.g., Cerulenin);phosphodiesterase (PDE) inhibitors (e.g., theophylline, pentoxifylline,zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram andcilomilast); thyroid hormone β agonists; uncoupling protein activators(UCP-1, 2 or 3) (e.g., phytanic acid,4-[(E)-2-(5,6,7,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acidand retinoic acid); acyl-estrogens (e.g., oleoyl-estrone);glucocorticoid antagonists; 11-beta hydroxy steroid dehydrogenase type 1(11β HSD-1) inhibitors; melanocortin-3 receptor (Mc3r) agonists; andstearoyl-CoA desaturase-1 (SCD-1) compounds.

Non-limiting examples of nutrient absorption inhibitors useful in thepresent methods for treating or preventing a Condition include lipaseinhibitors (e.g., orlistat, lipstatin, tetrahydrolipstatin, teasaponinand diethylumbelliferyl phosphate); fatty acid transporter inhibitors;dicarboxylate transporter inhibitors; glucose transporter inhibitors;and phosphate transporter inhibitors.

Non-limiting examples of cholesterol biosynthesis inhibitors useful inthe present methods for treating or preventing a Condition includeHMG-CoA reductase inhibitors, squalene synthase inhibitors, squaleneepoxidase inhibitors, and mixtures thereof.

Non-limiting examples of cholesterol absorption inhibitors useful in thepresent methods for treating or preventing a Condition includeezetimibe. In one embodiment, the cholesterol absorption inhibitor isezetimibe.

HMG-CoA reductase inhibitors useful in the present methods for treatingor preventing a Condition include, but are not limited to, statins suchas lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin,cerivastatin, CI-981, resuvastatin, rivastatin, pitavastatin,rosuvastatin or L-659,699((E,E)-11-[3′R-(hydroxy-methyl)-4′-oxo-2′R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoicacid).

Squalene synthesis inhibitors useful in the present methods for treatingor preventing a Condition include, but are not limited to, squalenesynthetase inhibitors; squalestatin 1; and squalene epoxidaseinhibitors, such as NB-598((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3′-bithiophen-5-yl)methoxy]benzene-methanaminehydrochloride).

Bile acid sequestrants useful in the present methods for treating orpreventing a Condition include, but are not limited to, cholestyramine(a styrene-divinylbenzene copolymer containing quaternary ammoniumcationic groups capable of binding bile acids, such as QUESTRAN® orQUESTRAN LIGHT® cholestyramine which are available from Bristol-MyersSquibb), colestipol (a copolymer of diethylenetriamine and1-chloro-2,3-epoxypropane, such as COLESTID® tablets which are availablefrom Pharmacia), colesevelam hydrochloride (such as WelChol® Tablets(poly(allylamine hydrochloride) cross-linked with epichlorohydrin andalkylated with 1-bromodecane and (6-bromohexyl)-trimethylammoniumbromide) which are available from Sankyo), water soluble derivativessuch as 3,3-ioene, N-(cycloalkyl) alkylamines and poliglusam, insolublequaternized polystyrenes, saponins and mixtures thereof. Suitableinorganic cholesterol sequestrants include bismuth salicylate plusmontmorillonite clay, aluminum hydroxide and calcium carbonate antacids.Probucol derivatives useful in the present methods for treating orpreventing a Condition include, but are not limited to, AGI-1067 andothers disclosed in U.S. Pat. Nos. 6,121,319 and 6,147,250.

IBAT inhibitors useful in the present methods for treating or preventinga Condition include, but are not limited to, benzothiepines such astherapeutic compounds comprising a 2,3,4,5-tetrahydro-1-benzothiepine1,1-dioxide structure such as are disclosed in International PublicationNo. WO 00/38727. Nicotinic acid receptor agonists useful in the presentmethods for treating or preventing a Condition include, but are notlimited to, those having a pyridine-3-carboxylate structure or apyrazine-2-carboxylate structure, including acid forms, salts, esters,zwitterions and tautomers, where available. Other examples of nicotinicacid receptor agonists useful in the present methods include nicotinicacid, niceritrol, nicofuranose and acipimox. An example of a suitablenicotinic acid product is NIASPAN® (niacin extended-release tablets)which are available from Kos Pharmaceuticals, Inc. (Cranbury, N.J.).Further nicotinic acid receptor agonists useful in the present methodsfor treating or preventing a Condition include, but are not limited to,the compounds disclosed in U.S. Patent Publication Nos. 2006/0264489 and2007/0066630, and U.S. patent application Ser. No 11/771,538, each ofwhich is incorporated herein by reference.

ACAT inhibitors useful in the present methods for treating or preventinga Condition include, but are not limited to, avasimibe, HL-004,lecimibide and CL-277082(N-(2,4-difluorophenyl)-N-[[4-(2,2-dimethylpropyl)phenyl]-methyl]-N-heptylurea).See P. Chang et al., “Current, New and Future Treatments inDyslipidaemia and Atherosclerosis”, Drugs 2000 July; 60(1); 55-93, whichis incorporated by reference herein.

CETP inhibitors useful in the present methods for treating or preventinga Condition include, but are not limited to, those disclosed inInternational Publication No. WO 00/38721 and U.S. Pat. No. 6,147,090,which are incorporated herein by reference.

LDL-receptor activators useful in the present methods for treating orpreventing a Condition include, but are not limited to, include HOE-402,an imidazolidinyl-pyrimidine derivative that directly stimulates LDLreceptor activity. See M. Huettinger et al., “Hypolipidemic activity ofHOE-402 is Mediated by Stimulation of the LDL Receptor Pathway”,Arterioscler. Thromb. 1993; 13:1005-12.

Natural water-soluble fibers useful in the present methods for treatingor preventing a Condition include, but are not limited to, psyllium,guar, oat and pectin.

Fatty acid esters of plant stanols useful in the present methods fortreating or preventing a Condition include, but are not limited to, thesitostanol ester used in BENECOL® margarine.

Non-limiting examples of antidiabetic agents useful in the presentmethods for treating a Condition include insulin sensitizers,α-glucosidase inhibitors, DPP-IV inhibitors, insulin secretagogues,hepatic glucose output lowering compounds, antihypertensive agents,sodium glucose uptake transporter 2 (SGLT-2) inhibitors, insulin andinsulin-containing compositions, and anti-obesity agents as set forthabove.

In one embodiment, the antidiabetic agent is an insulin secretagogue. Inone embodiment, the insulin secretagogue is a sulfonylurea.

Non-limiting examples of sulfonylureas useful in the present methodsinclude glipizide, tolbutamide, glyburide, glimepiride, chlorpropamide,acetohexamide, gliamilide, gliclazide, gliquidone, glibenclamide andtolazamide.

In another embodiment, the insulin secretagogue is a meglitinide.

Non-limiting examples of meglitinides useful in the present methods fortreating a Condition include repaglinide, mitiglinide, and nateglinide.

In still another embodiment, the insulin secretagogue is GLP-1 or aGLP-1 mimetic.

Non-limiting examples of GLP-1 mimetics useful in the present methodsinclude Byetta-Exanatide, Liraglutinide, CJC-1131 (ConjuChem,Exanatide-LAR (Amylin), BIM-51077 (Ipsen/LaRoche), ZP-10 (ZealandPharmaceuticals), and compounds disclosed in International PublicationNo. WO 00/07617.

Other non-limiting examples of insulin secretagogues useful in thepresent methods include exendin, GIP and secretin.

In another embodiment, the antidiabetic agent is an insulin sensitizer.

Non-limiting examples of insulin sensitizers useful in the presentmethods include PPAR activators or agonists, such as troglitazone,rosiglitazone, pioglitazone and englitazone; biguanidines such asmetformin and phenformin; PTP-1B inhibitors; and glucokinase activators.

In another embodiment, the antidiabetic agent is a α-Glucosidaseinhibitor.

Non-limiting examples of α-Glucosidase inhibitors useful the presentmethods include miglitol, acarbose, and voglibose.

In another embodiment, the antidiabetic agent is an hepatic glucoseoutput lowering agent.

Non-limiting examples of hepatic glucose output lowering agents usefulin the present methods include Glucophage and Glucophage XR.

In yet another embodiment, the antidiabetic agent is insulin, includingall formulations of insulin, such as long acting and short acting formsof insulin. Non-limiting examples of orally administrable insulin andinsulin containing compositions include AL-401 from Autoimmune, and thecompositions disclosed in U.S. Pat. Nos. 4,579,730; 4,849,405;4,963,526; 5,642,868; 5,763,396; 5,824,638; 5,843,866; 6,153,632;6,191,105; and International Publication No. WO 85/05029, each of whichis incorporated herein by reference.

In another embodiment, the antidiabetic agent is a DPP-IV inhibitor.

Non-limiting examples of DPP-IV inhibitors useful in the present methodsinclude sitagliptin, saxagliptin (Januvia™, Merck), denagliptin,vildagliptin (Galvus™, Novartis), alogliptin, alogliptin benzoate,ABT-279 and ABT-341 (Abbott), ALS-2-0426 (Alantos), ARI-2243 (Arisaph),BI-A and BI-B (Boehringer Ingelheim), SYR-322 (Takeda), MP-513(Mitsubishi), DP-893 (Pfizer), RO-0730699 (Roche) or a combination ofsitagliptin/metformin HCl (Janumet™, Merck).

In a further embodiment, the antidiabetic agent is a SGLT-2 inhibitor.

Non-limiting examples of SGLT-2 inhibitors useful in the present methodsinclude dapagliflozin and sergliflozin, AVE2268 (Sanofi-Aventis) andT-1095 (Tanabe Seiyaku).

Non-limiting examples of antihypertensive agents useful in the presentmethods for treating a Condition include β-blockers and calcium channelblockers (for example diltiazem, verapamil, nifedipine, amlopidine, andmybefradil), ACE inhibitors (for example captopril, lisinopril,enalapril, spirapril, ceranopril, zefenopril, fosinopril, cilazopril,and quinapril), AT-1 receptor antagonists (for example losartan,irbesartan, and valsartan), renin inhibitors and endothelin receptorantagonists (for example sitaxsentan).

In one embodiment, the antidiabetic agent is an agent that slows orblocks the breakdown of starches and certain sugars.

Non-limiting examples of antidiabetic agents that slow or block thebreakdown of starches and certain sugars and are suitable for use in thecompositions and methods of the present invention includealpha-glucosidase inhibitors and certain peptides for increasing insulinproduction. Alpha-glucosidase inhibitors help the body to lower bloodsugar by delaying the digestion of ingested carbohydrates, therebyresulting in a smaller rise in blood glucose concentration followingmeals. Non-limiting examples of suitable alpha-glucosidase inhibitorsinclude acarbose; miglitol; camiglibose; certain polyamines as disclosedin WO 01/47528 (incorporated herein by reference); voglibose.Non-limiting examples of suitable peptides for increasing insulinproduction including amlintide (CAS Reg. No. 122384-88-7 from Amylin;pramlintide, exendin, certain compounds having Glucagon-like peptide-1(GLP-1) agonistic activity as disclosed in International Publication No.WO 00/07617.

Other specific additional therapeutic agents useful in the presentmethods for treating or preventing a Condition include, but are notlimited to, rimonabant, 2-methyl-6-(phenylethynyl)-pyridine,3[(2-methyl-1,4-thiazol-4-yl)ethynyl]pyridine, Melanotan-II,dexfenfluramine, fluoxetine, paroxetine, fenfluramine, fluvoxamine,sertaline, imipramine, desipramine, talsupram, nomifensine, leptin,nalmefene, 3-methoxynaltrexone, naloxone, nalterxone, butabindide,axokine, sibutramine, topiramate, phytopharm compound 57, Cerulenin,theophylline, pentoxifylline, zaprinast, sildenafil, amrinone,milrinone, cilostamide, rolipram, cilomilast, phytanic acid,4-[(E)-2-(5,6,7,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid,retinoic acid, oleoyl-estrone, orlistat, lipstatin, tetrahydrolipstatin,teasaponin and diethylumbelliferyl phosphate.

In one embodiment, the present combination therapies for treating orpreventing diabetes comprise administering a Pyrimidine EtherDerivative, an antidiabetic agent and/or an antiobesity agent.

In another embodiment, the present combination therapies for treating orpreventing diabetes comprise administering a Pyrimidine Ether Derivativeand an antidiabetic agent.

In another embodiment, the present combination therapies for treating orpreventing diabetes comprise administering a Pyrimidine Ether Derivativeand an anti-obesity agent.

In one embodiment, the present combination therapies for treating orpreventing obesity comprise administering a Pyrimidine Ether Derivative,an antidiabetic agent and/or an antiobesity agent.

In another embodiment, the present combination therapies for treating orpreventing obesity comprise administering a Pyrimidine Ether Derivativeand an antidiabetic agent.

In another embodiment, the present combination therapies for treating orpreventing obesity comprise administering a Pyrimidine Ether Derivativeand an anti-obesity agent.

In one embodiment, the present combination therapies for treating orpreventing metabolic syndrome comprise administering a Pyrimidine EtherDerivative and one or more additional therapeutic agents selected from:anti-obesity agents, antidiabetic agents, any agent useful for treatingmetabolic syndrome, any agent useful for treating a cardiovasculardisease, cholesterol biosynthesis inhibitors, sterol absorptioninhibitors, bile acid sequestrants, probucol derivatives, IBATinhibitors, nicotinic acid receptor (NAR) agonists, ACAT inhibitors,cholesteryl ester transfer proten (CETP) inhibitors, low-densitylipoprotein (LDL) activators, fish oil, water-soluble fibers, plantsterols, plant stanols and fatty acid esters of plant stanols.

In one embodiment, the additional therapeutic agent is a cholesterolbiosynthesis inhibitor. In another embodiment, the cholesterolbiosynthesis inhibitor is a squalene synthetase inhibitor. In anotherembodiment, the cholesterol biosynthesis inhibitor is a squaleneepoxidase inhibitor. In still another embodiment, the cholesterolbiosynthesis inhibitor is an HMG-CoA reductase inhibitor. In anotherembodiment, the HMG-CoA reductase inhibitor is a statin. In yet anotherembodiment, the statin is lovastatin, pravastatin, simvastatin oratorvastatin.

In one embodiment, the additional therapeutic agent is a cholesterolabsorption inhibitor. In another embodiment, the cholesterol absorptioninhibitor is ezetimibe.

In one embodiment, the additional therapeutic agent comprises acholesterol absorption inhibitor and a cholesterol biosynthesisinhibitor. In another embodiment, the additional therapeutic agentcomprises a cholesterol absorption inhibitor and a statin. In anotherembodiment, the additional therapeutic agent comprises ezetimibe and astatin. In another embodiment, the additional therapeutic agentcomprises ezetimibe and simvastatin.

In one embodiment, the present combination therapies for treating orpreventing metabolic syndrome comprise administering a Pyrimidine EtherDerivative, an antidiabetic agent and/or an antiobesity agent.

In another embodiment, the present combination therapies for treating orpreventing metabolic syndrome comprise administering a Pyrimidine EtherDerivative and an antidiabetic agent.

In another embodiment, the present combination therapies for treating orpreventing metabolic syndrome comprise administering a Pyrimidine EtherDerivative and an anti-obesity agent.

In one embodiment, the present combination therapies for treating orpreventing a cardiovascular disease comprise administering one or morePyrimidine Ether Derivatives, and an additional agent useful fortreating or preventing a cardiovascular disease.

When administering a combination therapy to a patient in need of suchadministration, the therapeutic agents in the combination, or apharmaceutical composition or compositions comprising the therapeuticagents, may be administered in any order such as, for example,sequentially, concurrently, together, simultaneously and the like. Theamounts of the various actives in such combination therapy may bedifferent amounts (different dosage amounts) or same amounts (samedosage amounts).

In one embodiment, the one or more Pyrimidine Ether Derivatives areadministered during a time when the additional therapeutic agent(s)exert their prophylactic or therapeutic effect, or vice versa.

In another embodiment, the one or more Pyrimidine Ether Derivatives andthe additional therapeutic agent(s) are administered in doses commonlyemployed when such agents are used as monotherapy for treating aCondition.

In another embodiment, the one or more Pyrimidine Ether Derivatives andthe additional therapeutic agent(s) are administered in doses lower thanthe doses commonly employed when such agents are used as monotherapy fortreating a Condition.

In still another embodiment, the one or more Pyrimidine EtherDerivatives and the additional therapeutic agent(s) act synergisticallyand are administered in doses lower than the doses commonly employedwhen such agents are used as monotherapy for treating a Condition.

In one embodiment, the one or more Pyrimidine Ether Derivatives and theadditional therapeutic agent(s) are present in the same composition. Inone embodiment, this composition is suitable for oral administration. Inanother embodiment, this composition is suitable for intravenousadministration.

The one or more Pyrimidine Ether Derivatives and the additionaltherapeutic agent(s) can act additively or synergistically. Asynergistic combination may allow the use of lower dosages of one ormore agents and/or less frequent administration of one or more agents ofa combination therapy. A lower dosage or less frequent administration ofone or more agents may lower toxicity of the therapy without reducingthe efficacy of the therapy.

In one embodiment, the administration of one or more Pyrimidine EtherDerivatives and the additional therapeutic agent(s) may inhibit theresistance of a Condition to these agents.

In one embodiment, when the patient is treated for diabetes or adiabetic complication, the additional therapeutic agent is anantidiabetic agent which is not a Pyrimidine Ether Derivative. Inanother embodiment, the additional therapeutic agent is an agent usefulfor reducing any potential side effect of a Pyrimidine Ether Derivative.Such potential side effects include, but are not limited to, nausea,vomiting, headache, fever, lethargy, muscle aches, diarrhea, generalpain, and pain at an injection site.

In one embodiment, the additional therapeutic agent is used at its knowntherapeutically effective dose. In another embodiment, the additionaltherapeutic agent is used at its normally prescribed dosage. In anotherembodiment, the additional therapeutic agent is used at less than itsnormally prescribed dosage or its known therapeutically effective dose.

The doses and dosage regimen of the other agents used in the combinationtherapies of the present invention for the treatment or prevention of aCondition can be determined by the attending clinician, taking intoconsideration the the approved doses and dosage regimen in the packageinsert; the age, sex and general health of the patient; and the type andseverity of the viral infection or related disease or disorder. Whenadministered in combination, the Pyrimidine Ether Derivative(s) and theother agent(s) for treating diseases or conditions listed above can beadministered simultaneously or sequentially. This particularly usefulwhen the components of the combination are given on different dosingschedules, e.g., one component is administered once daily and anotherevery six hours, or when the preferred pharmaceutical compositions aredifferent, e.g. one is a tablet and one is a capsule. A kit comprisingthe separate dosage forms is therefore advantageous. Generally, a totaldaily dosage of the one or more Pyrimidine Ether Derivatives and theadditional therapeutic agent(s)can when administered as combinationtherapy, range from about 0.1 to about 2000 mg per day, althoughvariations will necessarily occur depending on the target of thetherapy, the patient and the route of administration. In one embodiment,the dosage is from about 0.2 to about 100 mg/day, administered in asingle dose or in 2-4 divided doses. In another embodiment, the dosageis from about 1 to about 500 mg/day, administered in a single dose or in2-4 divided doses. In another embodiment, the dosage is from about 1 toabout 200 mg/day, administered in a single dose or in 2-4 divided doses.In still another embodiment, the dosage is from about 1 to about 100mg/day, administered in a single dose or in 2-4 divided doses. In yetanother embodiment, the dosage is from about 1 to about 50 mg/day,administered in a single dose or in 2-4 divided doses. In a furtherembodiment, the dosage is from about 1 to about 20 mg/day, administeredin a single dose or in 2-4 divided doses.

Compositions and Administration

In one embodiment, the invention provides compositions comprising aneffective amount of one or more Pyrimidine Ether Derivatives or apharmaceutically acceptable salt, solvate, ester, prodrug orstereoisomer thereof, and a pharmaceutically acceptable carrier.

For preparing compositions comprising one or more Pyrimidine EtherDerivatives, inert, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,dispersible granules, capsules, cachets and suppositories. The powdersand tablets may be comprised of from about 5 to about 95 percent activeingredient. Suitable solid carriers are known in the art, e.g. magnesiumcarbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders,cachets and capsules can be used as solid dosage forms suitable for oraladministration. Examples of pharmaceutically acceptable carriers andmethods of manufacture for various compositions may be found in A.Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition,(1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

In one embodiment, a Pyrimidine Ether Derivative is administered orally.In one embodiment, the pharmaceutical preparation is in a unit dosageform. In such form, the preparation is subdivided into suitably sizedunit doses containing appropriate quantities of the active component,e.g., an effective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation is fromabout 0.1 to about 2000 mg. Variations will necessarily occur dependingon the target of the therapy, the patient and the route ofadministration. In one embodiment, the unit dose dosage is from about0.2 to about 1000 mg. In another embodiment, the unit dose dosage isfrom about 1 to about 500 mg. In another embodiment, the unit dosedosage is from about 1 to about 100 mg/day. In still another embodiment,the unit dose dosage is from about 1 to about 50 mg. In yet anotherembodiment, the unit dose dosage is from about 1 to about 10 mg.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, the condition and size of the patient,as well as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 1000 mg/day, 1 mg/day to about 500 mg/day, 1 mg/day toabout 300 mg/day, 1 mg/day to about 75 mg/day, 1 mg/day to about 50mg/day, or 1 mg/day to about 20 mg/day, in one dose or in two to fourdivided doses.

When the invention comprises a combination of one or more PyrimidineEther Derivatives and an additional therapeutic agent, the two activecomponents may be co-administered simultaneously or sequentially, or asingle composition comprising one or more Pyrimidine Ether Derivativesand the additional therapeutic agent(s) in a pharmaceutically acceptablecarrier can be administered. The components of the combination can beadministered individually or together in any conventional dosage formsuch as capsule, tablet, powder, cachet, suspension, solution,suppository, nasal spray, etc. The dosage of the additional therapeuticagent can be determined from published material, and may range fromabout 1 to about 1000 mg per dose. In one embodiment, when used incombination, the dosage levels of the individual components are lowerthan the recommended individual dosages because of an advantageouseffect of the combination.

In one embodiment, the components of a combination therapy regimen areto be administered simultaneously, they can be administered in a singlecomposition with a pharmaceutically acceptable carrier.

In another embodiment, when the components of a combination therapyregimen are to be administered separately or sequentially, they can beadministered in separate compositions, each containing apharmaceutically acceptable carrier.

Kits

In one aspect, the present invention provides a kit comprising aneffective amount of one or more Compounds of Formula (I), or apharmaceutically acceptable salt or solvate of the compound and apharmaceutically acceptable carrier, vehicle or diluent.

In another aspect the present invention provides a kit comprising anamount of one or more Compounds of Formula (I), and an amount of one ormore additional therapeutic agents, wherein the combined amounts areeffective for enhancing the memory of a patient or effective fortreating or preventing a cognitive disorder in a patient.

When the components of a combination therapy regimen are to are to beadministered in more than one composition, they can be provided in a kitcomprising comprising: (a) one or more Compounds of Formula (I) togetherin a pharmaceutically acceptable carrier in a single container, or (b)one or more Compounds of Formula (I) in separate containers, each in apharmaceutically acceptable carrier, and (c) one or more additionaltherapeutic agents together in a pharmaceutically acceptable carrier ina single container or (d) one or more additional therapeutic agents inseparate containers, each in a pharmaceutically acceptable carrier; suchthat the active components of the combination therapy are present inamounts that render the combination therapeutically effective.

The present invention is not to be limited by the specific embodimentsdisclosed in the examples that are intended as illustrations of a fewaspects of the invention and any embodiments that are functionallyequivalent are within the scope of this invention. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art and are intendedto fall within the scope of the appended claims.

A number of references have been cited herein, the entire disclosures ofwhich are incorporated herein by reference.

What is claimed is:
 1. A compound having the formula:

wherein: Q is —C(O)O— or a bond; W is —C(O)—, —C(O)O— or —S(O)₂—; Y ishalo; R³ is alkyl, haloalkyl, cycloalkyl or -alkylene-O-alkyl; and R¹⁰is cycloalkyl or heteroaryl, either of which can be substituted with analkyl or halo group.
 2. The compound of claim 1, wherein W is —C(O)— or—C(O)O—.
 3. The compound of claim 1, wherein W is —S(O)₂—.
 4. Thecompound of claim 1, wherein R³ is methyl, ethyl, n-propyl, isopropyl,t-butyl, —CF₃, —CH₂CH₂OCH₃, —CH₂CH₂CF₃, cyclopropyl or cyclopentyl.
 5. Acompound having the structure:

or a pharmaceutically acceptable salt thereof.
 6. A compositioncomprising an effective amount of one or more compounds of claim 1 or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.
 7. A method for treating diabetesin a patient, the method comprising administering to the patient aneffective amount of one or more compounds of claim 1, or apharmaceutically acceptable salt thereof.
 8. The composition of claim 6,further comprising at least one additional therapeutic agent, whereinthe additional therapeutic agent is selected from an antidiabetic agentand an antiobesity agent.
 9. A compound which is:

or a pharmaceutically acceptable salt thereof.
 10. The compound of claim1 which is:

or a pharmaceutically acceptable salt thereof.